Lamins are intermediate filament proteins found only in the nuclei of all multicellular eukaryotes. They form stable filaments at the nuclear inner membrane and are fundamentally important for nuclear architecture, chromatin organization and transcriptional regulation of gene expression. Mammalian cells encode both A-type (LMNA) and B-type (LMNB) lamins, which are highly related but can be distinguished on a biochemical and functional basis. LMNA has 12 exons, is localized to human chromosome 1q21.2-q21.3 and generates two protein isoforms, Lamin A and Lamin C through alternative splicing of LMNA2. Together with the outer nuclear membrane and nuclear pore complexes, the inner nuclear membrane forms the nuclear envelope that separates the chromosomes from cytoplasm in eukaryotic cells [2]. Furthermore, Lamin A/C interacts with numerous other proteins, including tissue-specific transcription factors [7].
Laminopathies belong to a heterogeneous group of disorders caused by mutations in the lamin A/C gene (LMNA) that affects a specific combination of tissues, such as heart, skeletal muscle, tendons, neurons, adipocytes and bone. Over 180 different mutations in the LMNA gene have been described. The wide clinical heterogeneity caused by mutations in the LMNA gene supports the hypothesis that Lamin A/C protein performs multiple functions in different tissues. The diseases caused by the wide spectrum of LMNA gene mutations are characterized by the extreme variability of the clinical phenotypes, ranging from cardiac and skeletal myopathies to partial lipodystrophy, peripheral neuropathy, and premature aging. No clear genotype-phenotype correlation has been clarified, since the same mutation can cause different diseases in unrelated families [8-10] and even amongst family members [11, 12]. A recent study, using hierarchical cluster analysis for assembling laminopathies into classes based on organ system involvement, uncovered a non-random relationship between the class of laminopathy and the mutation. These positions were strongly associated (p<0.0001) with the nuclear localization signal sequence of Lamin A/C [13].
One of the seven known laminopathies results in dilated cardiomyopathy (DCM) and is associated with at least eight different clustered missense in the rod 1 domain of Lamin A/C. Alteration of lamin A/C interaction(s) with heart specific factor(s) may be responsible for the pathogenesis of DCM laminopathies. However, the molecular pathogenesis from mutations in the LMNA gene to dilated cardiomyopathy with conduction disease is relatively unknown. Further, the molecular mechanisms for the relationship between tissue specificity of laminopathies and mutations in the LMNA gene are not understood. There remains a need to understand how these different pathologies arise from alterations in the same gene (LMNA) that is almost ubiquitously expressed in adult cells.
The diagnosis of the DCM type of laminopathy is particularly important because of the severity of the cardiac symptoms, which are characterized by conduction system defects, arrhythmias, left ventricular dysfunction, and dilation causing heart failure and subsequent death [14]. Conduction system disease may be observed in the absence of cardiomyopathy [9, 19, 20] or it may proceed cardiac dilation [21]. Severe progression of conduction system disease in laminopathies is typically characterized by sinus node dysfunction, progressive atrioventricular blockage, paroxysmal atrial fibrillation, and frequent premature ventricular beats [8, 9, 17, 20, 22-27]. About half of affected patients suffer sudden cardiac death due to lethal ventricular tachyarrhythmias, despite pacemaker implantation [8, 17, 25, 27-29]. Fibrofatty infiltration of the sinoatrial and the atrioventricular node, as well as the atrioventricular bundle have been described in humans with LMNA mutations as histopathological correlation to their cardiac conduction system disease [22, 24, 25, 30].
Several hypotheses have been proposed for the pathogenesis of laminopathies and most research has been focused on the ‘mechanical stress’ and ‘altered gene regulation’ hypotheses. The structural integrity of the nucleus may be affected by the expression of mutant A-type lamins. The fragility of the nuclear envelope is believed to contribute (in part) to pathologies in tissues subject to mechanical stresses, such as skeletal and cardiac muscle. The complete loss of A-type lamins supports this hypothesis.
Many of the proteins that are involved in chromatin organization, transcription and binding to DNA are either directly or indirectly associated with the nuclear envelope. Chromatin organization and transcriptional regulation of gene expression is, therefore, affected in specific ways due to the disruption of the nuclear envelope [34].
The mechanisms by which specific tissue are dramatically affected in laminopathies are not yet known. Knowledge of novel cardiac specific proteins that specifically interacts with lamin A/C would provide a means for diagnosing and treating the pathogenesis of cardiovascular disease and, more particularly, dilated cardiomyopathy with conduction disease.